EP0820292B1 - Inhibition d'infections par c. difficile a l'aide d'oligosaccharides indigestibles - Google Patents

Inhibition d'infections par c. difficile a l'aide d'oligosaccharides indigestibles Download PDF

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EP0820292B1
EP0820292B1 EP96912568A EP96912568A EP0820292B1 EP 0820292 B1 EP0820292 B1 EP 0820292B1 EP 96912568 A EP96912568 A EP 96912568A EP 96912568 A EP96912568 A EP 96912568A EP 0820292 B1 EP0820292 B1 EP 0820292B1
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difficile
fos
diarrhea
colitis
antibiotic
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EP0820292A1 (fr
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Keith Allen Garleb
Brian Warren Wolf
Jonathan Allan Meulbroek
Keith Brian Wheeler
Shelia Martinson Campbell
Joseph Edward Walton
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Abbott Laboratories
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Priority claimed from US08/417,411 external-priority patent/US5733579A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • This invention relates to the use of indigestible oligosaccharides for the inhibition of disease states associated with Clostridium difficile , and to an oral rehydration solution compositions containing indigestible oligosaccharides.
  • C. difficile is the leading known cause of nosocomial infections. Greenough et al., "Diarrhea in the elderly”, PRINCIPLES OF GERIATRIC MEDICINE AND GERONTOLOGY, Hazzard, et al., (ed) New York, McGraw-Hill, pp 1168-1176 (1990); McFarland et al., "A Randomized Placebo-Controlled Trial of Saccharomyces boulardii in Combination with Standard Antibiotics for Clostridium difficile Disease", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 271(24):1913-1918 (1994). The greatest risk of obtaining C.
  • C. difficile infection usually involves a surgical procedure (normally gastrointestinal in nature) combined with antibiotic therapy. Often, diets consumed by such patients are not conducive to either establishment or maintenance of the normal intestinal bacteria. In addition, C. difficile may be endemic in long-term care facilities for the elderly where outbreaks of diarrhea are common. Bender et al., "Is Clostridium difficile endemic in chronic-care facilities?", THE LANCET, 2:11-13 (1986).
  • C. difficile is a spore-forming, obligate anaerobic bacillus. It is a component of the normal intestinal flora of about 3% to 5% of healthy adults, but can be found in the stools of up to 15% to 20% of adults who are patients in hospitals and as many as 50% of asymptomatic infants. Fekety, "Antibiotic-Associated Diarrhea", DIARRHEAL DISEASES, ed. Field, pp. 293-317 (1991).
  • C. difficile When established in the colon, pathogenic strains of C. difficile produce toxins that are the cause of diarrhea and colitis. Banno et al., "Two toxins (D-1 and D-2) of Clostridium difficile causing antibiotic-associated colitis: Purification and some characterization", BIOCHEMISTRY INTERNATIONAL, 2:625-635 (1981); Taylor et al., "Comparison of two toxins produced by Clostridium difficile ", INFECTION AND IMMUNITY , 34:1036-1043 (1981). C. difficile produces two large protein exotoxins known as toxin A and toxin B. Toxin A causes fluid secretion, mucosal damage, and intestinal inflammation when injected into rodent intestine.
  • Triadafilopoulos et al. "Differential effects of Clostridium difficile toxins A and B on rabbit ileum", GASTROENTEROLOGY, 93:273-279 (1987).
  • Toxin B is more potent than toxin A as a cytotoxin in tissue culture, but is not enterotoxic in animals.
  • Kelly et al. "Clostridium difficile Colitis", THE NEW ENGLAND JOURNAL OF MEDICINE , 330(4):257-262 (1994). Dehydration as a result of diarrhea often follows C. difficile infection.
  • Toxin A (known as Toxin D-2 in the Japanese literature) is an enterotoxin and is considered the primary mediator of C. difficile -associated disease. It has a molecular weight (MW) of approximately 308,000.
  • Toxin B (known as Toxin D-1 in the Japanese literature) is a cytotoxin and has a molecular weight of approximately 270,000. It is believed that Toxin A causes tissue damage within the gastrointestinal tract and this damage is exacerbated by Toxin B resulting in diarrhea and colitis.
  • C. difficile colitis occurs at all ages, but is most frequent in elderly and debilitated patients.
  • C. difficile as a nosocomial pathogen is facilitated by the ease with which it is transmitted within the hospital environment and by the widespread use of antibiotics.
  • Antibiotics given for the treatment of even minor infections and administered by any route may precipitate PMC.
  • Practically every antimicrobial used in the treatment of human infections, including those most commonly used in the treatment of the disease, is known to incite PMC.
  • PMC may occur during the period immediately (almost always within 6 weeks) after the use of antibiotics have been discontinued, during this period, the normal intestinal flora has not yet reached normal levels, this absence of normal flora permits C. difficile to grow to unhealthy population levels.
  • the standard treatment for C. difficile -associated disease is administration of the antibiotics vancomycin or metronidazole. No new antibiotic treatments have proven to be effective in clinical trials.
  • an oral rehydration solution comprising sodium, potassium, chloride, a source of bicarbonate and an indigestible oligosaccharide that is resistant to endogenous digestion in the human upper digestive tract.
  • the oligosaccharide is a fructooligosaccharide, such as 1-ketose, nystose or 1 F - ⁇ -fructofuranose or a xylooligosaccharide, such as xylobiose, xylotriose or xylotetrose.
  • Fluid therapy may be either oral or intravenous, depending on the severity of dehydration. Oral rehydration solutions are less costly than intravenous therapy. Once this has been achieved other therapeutic concerns can be addressed.
  • indigestible oligosaccharide refers to a small carbohydrate moiety (Degree of polymerization less than 20 and/or a molecular weight less than 3,600) that is resistant to endogenous digestion in the human upper digestive tract.
  • Indigestible oligosaccharides that may be employed in preferred embodiments of the invention are fructooligosaccharides and xylooligosaccharides.
  • Indigestible oligosaccharides that may be employed in most preferred embodiments of the invention are fructooligosaccharides selected from the group consisting of 1-ketose, nystose and 1 F - ⁇ -fructofuranosyl nystose fructooligosaccharides, and xylooligosaccharides selected from the group consisting of xylobiose, xylotriose and xylotetrose xylooligosaccharides.
  • inhibiting is understood to refer to both reducing the number of C. difficile and preventing an increase in the number of C. difficile .
  • Fructooligosaccharides are carbohydrate polymers consisting of a chain of fructose residues linked by (2 ⁇ 1)- ⁇ -glucosidic bonds and usually carry a single D-glucosyl residue at the non-reducing end of the chain linked (1 ⁇ 2)- ⁇ - as in sucrose.
  • FOS occur in nature in many kinds of plants including bananas, tomatoes, onions, wheat, barley, honey, asparagus and artichokes. They can also be synthesized from sucrose through the use of transfructosylating enzymes, such as the enzyme obtained from the fungus Aspergillus niger. Hidaka et al., "Fructooligosaccharides: Enzymatic Preparation and Biofunctions", JOURNAL OF CARBOHYDRATE CHEMISTRY , 10(4):509-522 (1991). Treatment of sucrose with this enzyme results in a mixture of fructooligosaccharides containing 2, 3, or 4 fructose residues.
  • the resulting fructooligosaccharides are designated respectively 1-ketose (GF 2 ), nystose (GF 3 ), and 1 F - ⁇ -fructofuranosyl nystose (GF 4 ), the chemical structures of which are depicted in Fig.1.
  • GF 2 1-ketose
  • GF 3 nystose
  • GF 4 F - ⁇ -fructofuranosyl nystose
  • FOS are not hydrolyzed in the small intestine by rat or human digestive enzymes and thus reach the large intestine intact. There, many intestinal microorganisms utilize them. FOS can be utilized most significantly by bifidobacteria, which are believed to be highly beneficial organisms (Hidaka et al.). They cannot be utilized in vitro by certain undesirable, putrefactive bacteria such as C. perfringens, C. difficile , or E. coli.
  • Carbohydrates which are not digested in the small intestine can be fermented to short chain fatty acids by the microorganisms found in the large intestine.
  • the short chain fatty acids are used as an energy source for colonocytes and other organs such as the liver.
  • FOS have also been shown to reduce total serum cholesterol, probably by reducing the level of LDL-cholesterol, and to alleviate constipation by accelerating peristaltic movement (Hidaka et al.).
  • Xylooligosaccharides are prepared by the enzymatic hydrolysis of the xylan from corn, sugar cane, and cottonseed. Xylans are hydrolyzed by a Trichoderma -derived enzyme xylanase to make XOS. Xylooligosaccharides are mainly composed of two, three and four xylose units with a ⁇ -1-4 linkage, xylobiose, xylotriose, and xylotetrose, respectively the chemical structures of which are depicted in Fig. 2. Xylobiose, the main component of XOS, is relatively abundant in bamboo shoots.
  • XOS like FOS, have been shown to be selectively utilized by Bifidobacteria in vitro Okazaki et al., "Effect of xylooligosaccharide on the growth of bifidobacteria", BIFIDOBACTERIA MICROFLORA , 9(2):77-86 (1990).
  • clinical studies have shown that XOS, when supplemented to human diets, increase the level of bifidobacteria recovered in the feces (Okazaki et al).
  • in vitro studies demonstrate that potential pathogens like Staphylococcus, E. coli, C. perfringens, and C. difficile are not able to utilize XOS as an energy source (Okazaki et al).
  • SCFA short chain fatty acids
  • acetate, propionate, and butyrate short chain fatty acids
  • Short chain fatty acids play a key role in bowel function.
  • the absorption of 100 mmole SCFA is associated with the absorption of 360 ml water.
  • Casparey et al. "Bacterial fermentation of carbohydrates within the gastrointestinal tract", CLINICAL RESEARCH REVIEW , 1:107-177 (1981). Subsequently, the absence or reduction of SCFA in the colon could result in diarrhea. Ramakrishna et al.
  • Bowling et al. "Colonic secretory effect in response to enteral feeding in man", GUT , 34(suppl. 1):A54 (1993); Bowling et al., "The colonic secretory response to enteral feeding: influence of high strength diet", CLINICAL NUTRITION , 12(suppl. 2):23 (1993). Bowling et al., "Reversal by short-chain fatty acids of colonic fluid secretion induced by enteral feeding", LANCET , 342:1266 (1993) investigated the effect of short chain fatty acids on colonic fluid secretion induced by enteral feed. The researchers found that SCFA infusion directly into the cecum of healthy subjects reversed the fluid secretion seen in the ascending colon during enteral feeding and theorized that these findings could have implications for the management of diarrhea related to enteral feedings.
  • indigestible oligosaccharides like XOS and FOS
  • beneficial intestinal bacteria leads to an increase in the presence of bifidobacteria and results in the production of short chain fatty acids, which may lower pH in the large intestine, and suppress undesirable microorganisms and the substances (e.g., toxins) they produce. These activities would be beneficial to both human and animal health.
  • C. difficile -associated diarrhea may be treated, inhibiting the level of Toxin A, and also treating the associated dehydration, by enterally administering indigestible oligosaccharides in nutritional composition. While other nutritional compositions are certainly within the scope of the invention, ideally such nutritional compositions are oral rehydration solutions to help alleviate the dehydration associated with diarrhea.
  • the World Health Organization Oral Rehydration Solution (WHO-ORS) is a model ORS developed expressly to treat dehydration associated with diarrhea. It has a specific composition that, unlike water or other common household beverages, facilitates rehydration. The ideal sodium content of ORS is undecided.
  • the WHO-ORS contains 90 mEq of sodium per liter, but other ORS containing lower amounts have been demonstrated to be effective. Two typical, commercially available oral rehydration solutions are described below.
  • EquaLyteTM A widely used, commercially available oral rehydration solution for adults is EquaLyteTM which is distributed by the Ross Products Division of Abbott Laboratories, Columbus, Ohio, U.S.A.
  • EquaLyteTM provides: Sodium (mEq) 78.2 Potassium (mEq) 22.3 Chloride (mEq) 67.6 Citrate (mEq) (a source of bicarbonate) 30.1 Dextrose (g) 25 Calories 100
  • Pedialyte® A widely used, commercially available oral rehydration solution for infants and children is Pedialyte® which is distributed by the Ross Products Division of Abbott Laboratories, Columbus, Ohio, U.S.A. In 1000 mL, Pedialyte® provides: Sodium (mEq) 75 Potassium (mEq) 20 Chloride (mEq) 65 Citrate (mEq) (a source of bicarbonate) 30 Dextrose (g) 25 Calories 100
  • the present invention involves the addition of one or more indigestible oligosaccharides to an oral rehydration solution such as those described above. More specifically, the present invention may be practiced by adding about 3-30 g/L (preferably about 3-18 g/L of fructooligosaccharides to an oral rehydration solution such as EquaLyteTM or Pedialyte® which are described in the foregoing text.
  • an oral rehydration solution comprising sodium, potassium, chloride, a source of bicarbonate, and a therapeutically effective amount of an indigestible oligosaccharide.
  • the indigestible oligosaccharide may be selected from the fructooligosaccharides (e.g.
  • mice Female golden Syrian hamsters (6-8 weeks old, 80-120 g) were purchased from Harlan Sprague Dawley, Inc., Indianapolis, IN. Animals were randomly allotted to treatment groups and housed at 22 ⁇ 2°C in group housing. They were obtained pathogen free and housed in accordance with the Institutional Animal Care Use Committee (IACUC) and the American Association for the Accreditation of Laboratory Animal Care (AAALAC) standards. Animals were fed a standard lab chow diet (PROLAB®, Agway Country Foods, Inc., Syracuse, NY).
  • IACUC Institutional Animal Care Use Committee
  • AAAALAC American Association for the Accreditation of Laboratory Animal Care
  • Antibiotic Hamsters were medicated by daily gavage with ciprofloxacin (Miles, Inc., West Haven, CT; 250 mg/kg of body weight/day) on day 0 through day 6. This medication results in an "antibiotic sterilization" of the gastrointestinal tract which allows natural infection (overgrowth) of C. difficile . This "natural” infection can be unreliable under a laboratory setting, thus for a consistent degree of infection between animals additional treatments were added to our experiments to include inoculation (challenge) of hamsters with C. difficile on day 3 and day 7.
  • VPI 10463 was grown in BHI (brain heart infusion, Difco Laboratories, Detroit, MI) broth on a rotating platform under anaerobic conditions.
  • An overnight culture (ONC) has a concentration of about 10 9 CFU/mL.
  • Hamsters were inoculated with their respective volume of ONC via gavage on day 3 and day 7.
  • 63 hamsters were randomly allotted among 1 of 8 treatment groups. Treatments were arranged in a 2 x 2 x 2 factorial with 2 levels of FOS (0 or 30 g/L in drinking water), 2 levels of C. difficile inoculum (0 or 2.0 mL), and 2 levels of vancomycin (Eli Lilly, Indianapolis, IN) medication (0 or 50 mg/kg of body weight/day). FOS level, ciprofloxacin dose and inoculation protocol were similar to experiment 1. Hamsters on the vancomycin treatment were given 50 mg/kg of body weight/day on days 7 through 13.
  • MST Median survival time
  • FOS had a highly significant effect (P less than 0.1) on MST. Furthermore, separating out the inoculation level (0.5 and 2.0 mL) resulted in a larger MST for hamsters receiving supplemental FOS (P less than .01). Survival curves for hamsters inoculated with 0.5 and 2.0 mL C. difficile are presented in Figures 3 and 4, respectively. These figures show the improved survival time of hamsters fed supplemental FOS. Overall, FOS tended to increase (P less than .10) median survival time (MST). In addition, MST was increased (P less than .01) for hamsters consuming FOS which were inoculated with 0.5 or 2.0 mL of C.
  • FOS supplementation increased MST of non-inoculated hamsters treated or not treated with Vancomycin (P less than .05 and P less than .01, respectively; survival curves, Fig. 5 and 6, respectively). Again, survival curves show the added benefits of FOS. Overall, hamsters fed FOS had increased (P less than .05) MST.
  • MEDIAN SURVIVAL TIME OF HAMSTERS FED (+/-) 30 g/L FRUCTOOLIGOSACCHARIDES (FOS) IN DRINKING WATER AND CHALLENGED WITH VARYING LEVELS OF Clostridium difficile , AND TREATED (+/-) WITH VANCOMYCIN Group # n Inoculation FOS in H 2 O Vancomycin MST (days) 1 8 yes no no 13.0 2 8 yes no yes 20.0 3 8 no no no yes 17.5 4 8 no no no 13.5 5 8 yes yes no 14.5 6 8 yes yes yes yes 19.0 7 7 no yes yes 19.0 8 8 no yes no 16.5 MEDIAN SURVIVAL TIME (MST) OF HAMSTERS FED (+/-) 30 g/L FRUCTOOLIGOSACCHARIDES (FOS) IN DRINKING WATER, CHALLENGED (+/-) WITH Clostridium difficile , AND TREATED (+/-) WITH VANCOMYCIN 30 g/L FOS CON
  • Experiment 3 was to determine the effect of feeding highly fermentable carbohydrate on C. difficile infection in a murine model that included antibiotic administration prior to pathogen ( C. difficile ) challenge.
  • the model involved the disruption of gut microbiota with the antibiotic cefoxitin followed by a challenge with C. difficile (VPI 10463).
  • mice Sixty-four male BALB/c mice (mean body weight 19.3 ⁇ 1.6g) were individually housed in stainless steel cages. Environmental conditions were controlled to provide a 12 h light cycle and a constant temperature of 24°C.
  • Clostridium difficile Bacterial strains and conditions. A known toxigenic strain of Clostridium difficile was used in this study. Wilson et al., "Gnotobiotic models for study of microbial ecology of Clostridium difficile and Escherichia coli", THE JOURNAL OF INFECTIOUS DISEASES , 153(3):547-551 (1986); Sullivan et al., "Purification and characterization of toxins A and B of Clostridium difficile ", INFECTION AND IMMUNITY, 35(3):1032-1040 (1982). The organism was maintained and grown in reinforced clostridial medium (RCM; Difco, Detroit, Michigan, U.S.A.) and standard cell suspensions used as inocula.
  • RCM reinforced clostridial medium
  • Cefoxitin Sigma Chemical Co., St. Louis, Missouri, U.S.A.
  • C. difficile Fecal counts of C. difficile (Table 5) were influenced by a diet x sampling day interaction (P ⁇ .01). At the onset of the experiment (day -7) there were no detectable counts of C. difficile ( ⁇ 10 4 CFU/g feces). Interestingly, after cefoxitin dosage (day -6) and by three days following pathogen inoculation, all mice, including the uninoculated mice, became infected with C. difficile to a certain degree. For mice fed the control diet, C. difficile continued to increase throughout the experiment. By six days post C. difficile inoculation, the control mice had the highest C. difficile counts (127.5 x 10 5 CFU/g feces) and mice fed FOS had the lowest counts (0).
  • mice with detectable toxin A were detected in feces from any mice.
  • C. difficile and toxin A were detected in virtually every mouse and those inoculated with C. difficile had the highest titers (10 4 ).
  • mice consuming the C and GA diets had greater than a 50% incidence of toxin A while mice consuming FOS and XOS had less than a 50% incidence of toxin A. Only mice consuming C or GA diets and inoculated with C.
  • mice do not develop the same lesions as do humans (PMC) a murine model can still provide meaningful in vivo data.
  • Studies of microbial interactions coupled with nutritional manipulations can contribute to the understanding of causative factors in C. difficile colonization and infection.
  • the information provides a better understanding of gastrointestinal microbial ecology.
  • the oligosaccharides suppressed growth of C. difficile and appeared to provide protection to the intestinal epithelial tissue.

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Claims (9)

  1. Solution de réhydratation orale comprenant du sodium, du potassium, du chlorure, une source de bicarbonate et un oligosaccharide indigestible qui est résistant à la digestion endogène dans le tube digestif supérieur humain.
  2. Solution de réhydratation orale selon la revendication 1, dans laquelle l'oligosaccharide est un fructooligosaccharide.
  3. Solution de réhydratation orale selon la revendication 1, dans laquelle l'oligosaccharide est un xylooligosaccharide.
  4. Solution de réhydratation orale selon la revendication 2, dans laquelle ledit fructooligosaccharide est choisi dans le groupe comprenant le 1-kestose, le nystose et le 1F-β-fructofuranosylnystose.
  5. Solution selon la revendication 3, dans laquelle ledit xylooligosaccharide est choisi dans le groupe comprenant le xylobiose, le xylotriose et le xylotétrose.
  6. Solution selon la revendication 2, dans laquelle ledit fructooligosaccharide indigestible est présent à une concentration de 3 à 30 grammes par litre de solution.
  7. Solution selon la revendication 3, dans laquelle ledit xylooligosaccharide est présent à une concentration de 3 à 30 grammes par litre de solution.
  8. Solution selon la revendication 2, dans laquelle ledit fructooligosaccharide indigestible est présent à une concentration de 3 à 18 grammes par litre de solution.
  9. Solution selon la revendication 3, dans laquelle ledit xylooligosaccharide est présent à une concentration de 3 à 18 grammes par litre de solution.
EP96912568A 1995-04-05 1996-04-04 Inhibition d'infections par c. difficile a l'aide d'oligosaccharides indigestibles Expired - Lifetime EP0820292B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US08/417,413 US5688777A (en) 1995-04-05 1995-04-05 Inhibition of C. difficile infections by indigestible oligosaccharides
US417413 1995-04-05
US417411 1995-04-05
US08/417,411 US5733579A (en) 1995-04-05 1995-04-05 Oral rehydration solution containing indigestible oligosaccharides
PCT/US1996/004665 WO1996031219A1 (fr) 1995-04-05 1996-04-04 Inhibition d'infections par c. difficile a l'aide d'oligosaccharides indigestibles

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EP0820292B1 true EP0820292B1 (fr) 2003-02-12

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AT (1) ATE232389T1 (fr)
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EP1166800B1 (fr) * 2000-06-28 2006-03-22 B.S.D. BIO SCIENCE DEVELOPMENT SNC Di OMINI C. & ZUCCARI G. Compositions pharmaceutiques contenant des antibiotiques et des mélanges de fructosane
EP1243273A1 (fr) † 2001-03-22 2002-09-25 Societe Des Produits Nestle S.A. Composition contenant un agent prebiotique pour le traitement d'inflammation et d'activation anormal des agents immunitaires non-spécifiques
EP1812042A1 (fr) * 2004-09-30 2007-08-01 University Technologies International Inc. Compositions rehydratantes comprenant un facteur de croissance epidermique
CN101668437A (zh) * 2007-03-13 2010-03-10 N.V.努特里奇亚 使用含有非消化性糖的组合物改善能力的方法
US20190070204A1 (en) * 2016-03-14 2019-03-07 B Food Science Co., Ltd. Proliferative agent for faecalibacterium

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US4902674A (en) * 1987-10-13 1990-02-20 Coors Biotech, Inc. Method for inhibiting the growth of salmonella
AU634746B2 (en) * 1989-02-07 1993-03-04 Dimminaco Ag/Sa/Ltd. Effervescent composition for oral rehydration
US5397786A (en) * 1993-01-08 1995-03-14 Simone; Charles B. Rehydration drink

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PT820292E (pt) 2003-06-30
JPH11503168A (ja) 1999-03-23
CA2217157C (fr) 2002-07-30
HK1008492A1 (en) 1999-05-14
CA2217157A1 (fr) 1996-10-10
NO974490L (no) 1997-09-29
AU704004B2 (en) 1999-04-01
NZ306712A (en) 1999-10-28
AU5534296A (en) 1996-10-23
DK0820292T3 (da) 2003-05-19
NO313685B1 (no) 2002-11-18
MX9707631A (es) 1998-04-30
ATE232389T1 (de) 2003-02-15
DE69626200T2 (de) 2003-12-18
EP0820292A1 (fr) 1998-01-28
DE69626200D1 (de) 2003-03-20
ES2194988T3 (es) 2003-12-01
NO974490D0 (no) 1997-09-29
WO1996031219A1 (fr) 1996-10-10

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